SB559457 (SB) is a non-peptidyl, hydrazone class, organic small molecule employed by GlaxoSmithKline (GSK) as a tool compound in the development of thrombopoietin receptor (c-Mpl) agonists. In the course of collaboration with GSK scientists to determine SB's biological activities, my laboratory observed that it was toxic to primary human myeloid leukemia cells. Eltrombopag, an orally available, FDA approved form of SB that is indicated for patients with refractory idiopathic thrombocytopenic purpura (ITP), and Hepatitis C associated thrombocytopenia, also proved toxic to myeloid leukemia cells. An orally available, well tolerated medication that stimulates thrombopoiesis at the same time that it kills myeloid leukemia cells could prove highly useful in the clinic, and might be particularly appropriate for elderly patients with AML and thrombocytopenia who were not candidates, or did not desire, traditional chemotherapy. We propose to test this hypothesis in the "Quick-Trials for Novel Cancer Therapies" R21 Exploratory Grant program and propose the following specific aims that will be carried out during the 2 year tenure of such an award. Specific Aim # 1- Determine the safety, tolerability and activity of single agent eltrombopag in elderly patients with AML. This will be tested in a single center Phase I/II clinical trial to be opened at the Hospital of the University of Pennsylvania. Specific Aim #2- Carry out Pharmacokinetic and Pharmacodynamic Studies on patients treated with Eltrombopag to determine its mechanism of action. Our preliminary studies have demonstrated that eltrombopag and thrombopoietin initiate different signal transduction cascades with resulting differing transcriptional responses. We hypothesize that these differences provide clues to eltrombopag's cytopathic effect on AML cells. Using cell samples derived from patients on study, we will investigate these responses to determine a mechanism of action for this class of drug. These studies will not only help provide a mechanism of action, but may also lead to the elucidation of novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Acute Myelogenous Leukemia has been treated with much the same drugs for the past quarter century. To improve the outcome for most patients, new treatment approaches are needed. The opportunity to evaluate the efficacy, and learn the mechanism of action, of a novel leukemia therapy with the very desirable qualities of being orally available and effective for treating, not causing, thrombocytopenia should be compelling.